A Phase Ib Study of Lapatinib in Combination with Caelyx in Patients with Advanced HER2 positive pretreated Breast Cancer.

Treatment Plan:

Lapatinib is given at escalating doses orally and continuously on days 1-21. Caelyx is administered at escalating doses in a 60-minute i.v. infusion on day 1. Each cycle is defined as 21 days. Four dose levels are planned. Dose level -1, Caelyx 30 mg/mq & Lapatinib 1000 mg die; dose level 1, Caelyx 30 mg/mq & Lapatinib 1250 mg die; dose level 2, Caelyx 30 mg/mq & Lapatinib 1500 mg die; dose level 3, Caelyx 40 mg/mq & Lapatinib 1500 mg die. Three patients will be initially enrolled in each dose level starting from level 1. If none of the first triplet of patients will develop DLT, the dose will be escalated to the next level for the subsequent three patients. If one of the first triplets of patients will develop first-course DLT, a maximum of 3 additional patients will be entered at the same dose level. The MTD is defined as the dose below that at which two patients have experienced DLT. Lapatinib will be self-administered by the patient in an outpatient setting at the dose of the assigned step. Patients will take the drug daily by mouth on days 1 to 21 of each cycle. Caelyx will be administered by intravenous infusion over an exact period of 1 hour (preferably by a pump to guarantee a constant speed of infusion) on day

1 of each cycle repeated every 21 days.

STATISTICAL METHODOLOGY:

Evaluation of toxicity: all patients will be evaluable for toxicity from the time of their first treatment with Caelyx and Lapatinib.

Evaluation of response: all patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible.

All conclusions should be based on all eligible patients. Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified .However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% confidence intervals should also be provided.

The MTD (Maximum Tolerated Dose) is defined as the dose below that at which two patients have experienced DLT (Dose Limiting Toxicity).

Secondary Outcome Measures:

Anti tumour activity of Lapatinib in combination with Caelyx in terms of Objective Response Rate (CR or PR). [ Time Frame: 6 years ] [ Designated as safety issue: No ]

Response and progression are evaluated using the RECIST Criteria (Response Evaluation Criteria In Solid Tumors).

Evaluation of toxicity. [ Time Frame: 6 years. ] [ Designated as safety issue: No ]

All patients will be evaluable for toxicity from the time of their first treatment with Caelyx and Lapatinib, using NCI-CTCAE v.3 (National cancer Institute - Common Terminology Criteria for Adverse Events).

Subjects must have tumors that overexpress ErbB2 defined as +3 by IHC or FISH positive for ErbB2 gene amplification. The status of ErbB2 expression must be documented prior to study entry.

Subjects must have disease progression (by RECIST) following prior therapy with taxane and trastuzumab-containing regimens (if not contraindicated).

Patients may have had any number of prior chemotherapy, immunotherapy, hormonal therapy, investigational or radiotherapy regimens, but therapy must be discontinued at least 4 weeks before study entry (6 weeks if the last regimen included BCNU or mitomycin C).

Age >18 years.

Life expectancy of greater than 12 weeks.

ECOG performance status <2 (see Appendix A).

Cardiac ejection fraction within the institutional range of normal as measured by echocardiogram (ECHO).

Previous anthracycline use inferior of 360 mg/mq for epirubicin and 200 mg/mq for doxorubicin (provided that patients have been off-treatment for at least one year and did not progress under treatment).

Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Ability to swallow and retain oral medications.

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Participation in another clinical trial with any investigational agents within 30 days prior to study screening.

Patients with symptomatic brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction, that would confound the evaluation of neurologic and other adverse events. Asymptomatic patients are allowed.

History of allergic reactions attributed to compounds of similar chemical or biologic composition to Caelyx and Lapatinib or other agents used in the study.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02131506